The objective of this study is to elucidate those early events in HIV infection that may lead to pathogenesis. Two important advances were made this last year.[unreadable] [unreadable] Macrophages are infected in the circulatory system as well as in the brain. We have identified the early innate immunological responses following HIV infection of primary human macrophages: induction of the chemokines CXCL8 and CXCL10. CXCL8 recruits neutrophils, which are the hallmark of acute inflammation and can mediate tissue damage; CXCL10, also generated by the HIV-infected macrophage, recruits activated CD4 T cells and more macrophages, which become productively infected by the macrophage HIV particles. [unreadable] [unreadable] HIV has evolved to use two chemokine co-receptors to infect macrophages, microglia, and T cells. One is CCR5, expressed on macrophages, microglia, and active, memory T cells. HIV readily infects these cells. The other co-receptor, CXCR4, is expressed on quiescent naive CD4 T cells, which are naturally resistant to retroviral infection; however, in AIDS patients the CXCR4-utilizing virus usually shows up late in the disease and commonly coincides with rapid deterioration. We have discovered that the interaction of HIV envelope with cell surface CXCR4 alters the cellular structural components to render these cells susceptible to infection. We have found that the signal from HIV engagement of the CXCR4 co-receptor activates cofilin, which leads to cortical actin rearrangements and HIV DNA delivery to the nucleus. This finding demonstrates an evolved selection of the co-receptor CXCR4 by HIV to alter the cellular biochemical environment so that it is supportive of infection, as well as suggests that defective viral particles, or circulating HIV envelope can in fact prime resting T cells for productive infection.[unreadable] [unreadable] Future efforts will include identifying the mechanism(s) of CXCL8 and CXCL10 induction by HIV infection of macrophages, and how this might contribute to pathogenesis. We will also continue our exploration of the biochemical activity of the Nef protein.